Evidence abounds that inflammatory mononuclear phagocyte iMP; microglial cells, perivascular and brain macrophage) secretory processes are centrally implicated in the neuropathogenesis of HIV-1-associated dementia (HAD). Whether this can be harnessed to positively affect neurodegenerative processes is less apparent. Thus, this program project (PPG) seeks support for investigating the specific immunologic basis of HAD and linkages between it and other neurodegenerative disorders. The focal point of disordered immunity for HAD is the microglia, the cell that links all PPG research efforts. The studies will utilize, as its foundation, a well-developed research infrastructure within the Center for Neurovirology and Neurodegenerative Disorders (CNND) of the University of Nebraska Medical Center. The CNND consists of investigators of diverse expertise who maintain a unified focus for their research on how MP biology affects both neurodegeneration and neuroprotection. This group of scientists has significant expertise in areas of neurotoxicology, cellular immunology, neuropathology, neurophysiology, neuropharmacology and molecular biology. "State of the art" technologies in magnetic resonance imaging/spectroscopy, electrophysiology, gene arrays and proteomics are being developed and strengthen this proposal. Currently, ties between innate and acquired immunity for brain MP function serve to bridge all of the proposed projects. It is our hypothesis that inflammatory mechanisms cause or intensify tissue damage during neurodegenerative processes. Most importantly, we believe these can be reversed through drug or immune manipulations. We purport that the interplay between the peripheral immune system and the brain serves to counter neuronal death caused as a result of viral infection. The balance between MP trophic and toxic activities may, therefore, underlie the process of dementia. The strength of this proposal is its well-developed cross-disciplinary program of young, energetic investigators whose scientific expertise spans the gantlet of MP-virus-neural interactions. Working under one roof, in one organizational structure with a strong track record of collaboration and joint publications should serve the PPG well in its quest to merge research initiatives designed to address pathogenic and therapeutic aspects of HAD. Results of these works should have implications for monitoring disease and in developing novel therapeutics (for example, Alzheimer's disease) which now has few treatment options.